Synthesis and Characterization of 5-MeO-DMT Succinate for Clinical Use

Alexander M Sherwood, Romain Claveau, Rafael Lancelotta, Kristi W Kaylo, Kelsey Lenoch, Alexander M Sherwood, Romain Claveau, Rafael Lancelotta, Kristi W Kaylo, Kelsey Lenoch

Abstract

To support clinical use, a multigram-scale process has been developed to provide 5-MeO-DMT, a psychedelic natural product found in the parotid gland secretions of the toad, Incilius alvarius. Several synthetic routes were initially explored, and the selected process featured an optimized Fischer indole reaction to 5-MeO-DMT freebase in high-yield, from which the 1:1 succinate salt was produced to provide 136 g of crystalline active pharmaceutical ingredient (API) with 99.86% peak area by high-performance liquid chromatography (HPLC) and a net yield of 49%. The report provides in-process monitoring, validated analytical methods, impurity formation and removal, and solid-state characterization of the API essential for subsequent clinical development.

Conflict of interest statement

The authors declare no competing financial interest.

© 2020 American Chemical Society.

Figures

Figure 1
Figure 1
Structures of clinically explored psychedelic, entactogenic, and dissociative psychoactive drugs.
Figure 2
Figure 2
(Left) I. alvarius (image courtesy of Holger Krisp, Ulm, Germany, 2011 under CC BY 3.0) with the parotid gland highlighted. (Right) Structure of 5-MeO-DMT (6).
Scheme 1. Eschweiler–Clarke Reaction to 6 and…
Scheme 1. Eschweiler–Clarke Reaction to 6 and Mechanism of Pictet–Spengler Byproduct Formation
Scheme 2. Speeter–Anthony Tryptamine Synthesis and Byproduct…
Scheme 2. Speeter–Anthony Tryptamine Synthesis and Byproduct Formation via Reactive Impurity 11
Scheme 3. (A) Fischer Indole Reaction in…
Scheme 3. (A) Fischer Indole Reaction in the preparation of 6 and (B) Approved Antimigraine Medications Prepared by the Analogous Process
Scheme 4. Formation of Degradant 18 Annotated…
Scheme 4. Formation of Degradant 18 Annotated With 1H NMR Shift for the Suspected Dichloromethane Adduct
Scheme 5. Putative Dimer Impurity Structure and…
Scheme 5. Putative Dimer Impurity Structure and MS/MS Fragmentation
Red circles indicate alternate attachment points.
Scheme 6. Synthesis of N-Oxide 21
Scheme 6. Synthesis of N-Oxide 21

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